Neurogenic hyperadrenergic orthostatic hypotension: a newly recognized variant of orthostatic hypotension in older adults with elevated norepinephrine (noradrenaline)

Abstract

Patients with neurogenic orthostatic hypotension (OH) typically have impaired sympathetic nervous system tone and therefore low levels of upright plasma norepinephrine (NE) (noradrenaline). We report a subset of patients who clinically have typical neurogenic OH but who paradoxically have elevated upright levels of plasma NE. We retrospectively studied 83 OH patients evaluated at the Vanderbilt Autonomic Dysfunction Center between August 2007 and May 2013. Based on standing NE, patients were dichotomized into a hyperadrenergic OH group [hyperOH: upright NE ≥ 3.55 nmol/l (600 pg/ml), n=19] or a non-hyperadrenergic OH group [nOH: upright NE < 3.55 nmol/l (600 pg/ml), n=64]. Medical history and data from autonomic testing, including the Valsalva manoeuvre (VM), were analysed. HyperOH patients had profound orthostatic falls in blood pressure (BP), but less severe than in nOH [change in SBP (systolic blood pressure): -53 ± 31 mmHg compared with -68 ± 33 mmHg, P=0.050; change in DBP (diastolic blood pressure): -18 ± 23 mmHg compared with -30 ± 17 mmHg, P=0.01]. The expected compensatory increase in standing heart rate (HR) was similarly blunted in both hyperOH and nOH groups [84 ± 15 beats per minute (bpm) compared with 82 ± 14 bpm; P=0.6]. HyperOH patients had less severe sympathetic failure as evidenced by smaller falls in DBP during phase 2 of VM and a shorter VM phase 4 BP recovery time (16.5 ± 8.9 s compared with 31.6 ± 16.6 s; P<0.001) than nOH patients. Neurogenic hyperOH patients have severe neurogenic OH, but have less severe adrenergic dysfunction than nOH patients. Further work is required to understand whether hyperOH patients will progress to nOH or whether this represents a different disorder.

Figure 1. Representative Valsalva maneuver traces

Continuous blood pressure tracings of a healthy subject (Panel a), a patient with hyperadrenergic orthostatic hypotension (hyperOH, Panel b), and a patient with non-hyperadrenergic orthostatic hypotension (nOH, Panel c) are shown. SBP- systolic blood pressure; PRT – pressure recovery time (see text or Figure 2 for details on calculation).

Figure 2. Schematic Parameterization of the Valsalva Maneuver

Valsalva maneuver from one of our orthostatic hypotension patients is shown with blood pressure displayed on top and expiratory Valsalva pressure on the bottom. Annotations include the baseline (bsl) systolic blood pressure (SBP) prior to the Valsalva maneuver, the peak SBP during Valsalva phase 1 (1p), the nadir of Valsalva phase 2 (2n), and the nadir of phase 3 (3n). Arrow (a) represents the Valsalva phase 2 SBP Decrement. Arrow (b) represents the difference between baseline SBP and the end of Valsalva phase 2n. Arrow (c) represents the difference between baseline SBP and point 3n. Pressure recovery time (PRT) is measured as the time from the nadir SBP of Valsalva phase 3 until SBP recovers back to bsl level at point (r). Adrenergic baroreflex sensitivity index (BRS-a) is equal to the SBP represented by arrow (c) divided by the PRT.

Figure 3. The distribution of upright plasma norepinephrine levels

The distribution of upright plasma norepinephrine into intervals of 0.30 nmol/L (50 pg/mL) is shown for our entire study population (n=83). A line has been drawn at 600 pg/mL to dichotomize our study population into a hyperadrenergic orthostatic hypotension group (hyperOH) to the left of the line, and a non-hyperadrenergic orthostatic hypotension group (nOH) to the right of the line. There is a normal distribution to the left of the line, with outliers to the right of this line.

Figure 4. Summary Valsalva Metrics between the patient groups

Summary Valsalva data are presented for hyperadrenergic orthostatic hypotension (hyperOH) and non-hyperadrenergic orthostatic hypotension (nOH) patients. The panels show Pressure Recovery Time (PRT; panel a), adrenergic baroreflex sensitivity (BRS-a; panel b), the fall in systolic blood pressure (SBP; panel c) and the fall in diastolic blood pressure (DBP; panel d) during phase 2 of the Valsalva maneuver. Data are presented as mean±standard error of the mean. Student’s t-tests were used to generate P values.